TITLE: ASYMMETRIC SYNTHESIS OF (S)-3-(l-(DIMETHYLAMINO) ETHYL) PHENYLETHYL(METHYL) CARBAMATE AND ITS SALTS. TECHNICAL FIELD

The present invention is in relation to pharmaceutical chemistry. In particular, the present invention is in relation to the preparation of (S)-3-(l-(dimethylamino)ethyl)phenylethyl (methyl) carbamate, commonly known as Rivastigmine. The method involves facile two step asymmetric synthesis to obtain the target compound through an enantioselective intermediate obtained in high purity.

BACKGROUND

Dementia, is a general term for memory loss and interference in activities that affects the daily life. Alzheimer's disease is one of the reasons for dementia, it is estimated that about 45 million are suffering from Alzheimer's disease and the estimated figure is consistently increasing. The disease is of concern to the society at large with the number of people being affected, more concerning fact is that there is no curative measures available and has to be managed with palliative measures.

(S)-3-(l-(dimethylamino)ethyl)phenylethyl(methyl)carbamat e, commonly known as Rivastigmine (Formula A) an acetylcholinesterase inhibitor, it is expected to inhibit the cholinesterase enzymes, which breaks down the brain neurotransmitter acetylcholine. Currently, Rivastigmine is the most recommended drug to manage patients with moderate dementia.

Formula A

Considering the importance of the drug, many methods of its preparation have been proposed in the literature. The patent document US4948807 has first described about the compound 3-(l- (dimethylamino)ethyl)phenylethyl(methyl)carbamate and US5602176 describes about the usage of S-isomer of 3-(l-(dimethylamino) ethyl) phenyl ethyl (methyl)carbamate as the acetylcholinestrase inhibitor. Since then most of the documents which has discussed about the preparation of said compound have addressed the challenge of the preparation of pharmaceutically active S-isomer of 3-(l-(dimethylamino)ethyl)phenylethyl(methyl)carbamate in high purity and yield.

While some of the literature focus on the preparation of racemic 3-(l- (dimethylamino)ethyl)phenylethyl(methyl)carbamate and then separate the isomers, the recent trend has been the preparation of the pharmaceutically active (S) isomer. WO2004/037771 discusses about the preparation of the racemic intermediate and separation of the isomers using S-(+)-camphor sulfonic acid.

Kiwon Han et al in . Org. Chem., 2010, 75 (9), pp 3105-3108, "Chemoenzymatic Synthesis of Rivastigmine via Dynamic Kinetic Resolution as a Key Step" describes about a procedure involving dynamic kinetic resolution using a polymer -bound ruthenium complex and a lipase in combination as a key step. The process involves five steps yielding overall 57% yield.

Pu-Cha Yan et al in Org. Process Res. Dev., 2013, 17 (2), pp 307-312, "Industrial Scale-Up of Enantioselective Hydrogenation for the Asymmetric Synthesis of Rivastigmine" describes process involving asymmetric hydrogenation by applying the chiral spiro catalyst, Ir-SpiroPAP, using high pressure hydrogen gas for chiral reduction. The synthetic route involved rivastigmine in four steps and 84% overall yield.

Madhuresh K. Sethi et al in Tetrahedron: Asymmetry, Volume 24, Issue 7, 15 April 2013, Pages 374-379, "Asymmetric synthesis of an enantiomerically pure rivastigmine intermediate using ketoreductase" provides a chemo-enzymatic synthesis of (5)-rivastigmine using ketoreductases with NADH/NADPH as the proton donor for the total synthesis of (S)-rivastigmine.

Veera R. Araval in 2011, 1, 26-32, International Journal of Organic Chemistry "A Simple and Highly Efficient Enantioselective Synthesis of (S)-Rivastigmine" demonstrates chemoenzymatic total synthesis of enantiopure (5)-Rivastigmine using various ω-transaminases through the asymmetric amination of appropriate acetophenone precursors.

The disclosures aim to provide enantiomerically pure (S)-3-(l-(dimethylamino)ethyl)phenylethyl (methyl)carbamate, the methods followed are tedious, expensive involving catalytic hydrogenation, separation of racemic mixtures and suffer from retarded industrial scalability of the reactions to obtain the target compound.

Hence it is aimed through the present invention to provide enantiomerically highly pure (S)-3-(l- (dimethylamino)ethyl)phenylethyl (methyl)carbamate through simple asymmetric reduction processes involving commercially available cost effective reagents. The industrially scalable method provides high yield of the compound economically. SUMMARY OF INVENTION

Accordingly, the present invention provides an asymmetric synthesis; involving an embodiment comprising reduction of 3-acetylphenyl ethyl(methyl)carbamate (I) to obtain selectively either (S) or (R)-3-(l-hydroxyethyl)phenyl ethyl(methyl)carbamate (II, Formula B) in the first step which is further converted to (S)-3-(l-(dimethylamino)ethyl)phenylethyl (methyl)carbamate in the second step using selectively Methanesulphonylchlonde in the presence of an amine in case of (R)-3-(l-hydroxyethyl) phenyl ethyl(methyl)carbamate or Potassium tribromide in the presence of an amine in case of (S)-3-(l-hydroxyethyl) phenyl ethyl(methyl)carbamate.

The reduction is carried out by two processes, first embodiment utilizes complex of pheyl boronic acid, Sodium borohydride and L(+) Tartaric acid or asymmetric metal catalyst of Dichloro(p-cymene)ruthenium(II)dimer and (RR)-N-(2-Amino-l,2-diphenylethyl)-p- toluenesulfonamide to obtain (R)-3-(l-hydroxyethyl) phenyl ethyl(methyl)carbamate.

The second embodiment utilizes of pheyl boronic acid, sodium borohydride and D(+) Tartaric acid or asymmetric metal catalyst of Dichloro(p-cymene)ruthenium(II)dimer and (SS)-N-(p- Toluenesulfonyl)- 1 ,2-diphenylethanediamine to obtain (S)-3-(l-hydroxyethyl) phenyl ethyl(methyl)carbamate.

The invention also relates to the preparation of pharmaceutically acceptable salts of (S)-3-(l- (dimethylamino)ethyl)phenylethyl (methyl)carbamate, specifically tartarate salt of high purity.

BRIEF DESCRIPTION OF FIGURES

The appended figures are provided to describe the invention in detail and does not limit the scope of the invention.

Figure 1 : HPLC Chromatogram indicating the purity of the R-Isomer from experiment 1.

Figure 2: HPLC Chromatogram indicating the enantiomeric purity of the isomers from experiment 1.

Figure 3: HPLC Chromatogram indicating the purity of the R-Isomer from experiment 2. Figure 4: HPLC Chromatogram indicating the enantiomeric purity of the isomers from experiment 2.

Figure 5: HPLC Chromatogram indicating the purity of the S -Isomer from experiment 3.

Figure 6: HPLC Chromatogram indicating the enantiomeric purity of the isomers from experiment 3.

Figure 7: HPLC Chromatogram indicating the purity of the S -Isomer from experiment 4.

Figure 8: HPLC Chromatogram indicating the enantiomeric purity of the isomers from experiment 4.

Figure 9: HPLC Chromatogram indicating the purity of the S -Isomer from experiment 5.

Figure 10: HPLC Chromatogram indicating the enantiomeric purity of the isomers from experiment 5.

Figure 11: HPLC Chromatogram indicating the purity of the S-Isomer from experiment 6.

Figure 12: HPLC Chromatogram indicating the enantiomeric purity of the isomers from experiment 6.

Figure 13: HPLC Chromatogram indicating the purity of the tartarate salt of S -Isomer from experiment 7.

Figure 14: HPLC Chromatogram indicating the enantiomeric purity of the tartarate salt of S- isomer from experiment 7.

Figure 15: HPLC Chromatogram indicating the purity of the tartarate salt of S -Isomer from experiment 8.

Figure 16: HPLC Chromatogram indicating the enantiomeric purity of the tartarate salt of S- isomer from experiment 8. DETAILED DESCRIPTION OF INVENTION

The foregoing description of the embodiments of the invention has been presented for the purpose of illustration. It is not intended to be exhaustive or to limit the invention to the precise form disclosed as many modifications and variations are possible in light of this disclosure for a person skilled in the art in view of the figures, description and claims. It may further be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by person skilled in the art.

The present invention is in relation to a method of preparation of (5)-3-(l- (dimethylamino)ethyl)phenylethyl(methyl) carbamate, said method comprising acts of

a) reducing stereospecifically 3-acetylphenyl ethyl(methyl)carbamate to 3-((R) 1- (hydroxyethyl) phenyl ethyl(methyl)carbamate by reacting with compound selected from a group comprising complex of Phenyl boronic acid- Sodium borohydride - L(+) Tartaric acid and Ruthenium metal catalyst- prepared by reacting with Dichloro(p-cymene) ruthenium(II)dimer and (i?,i?-N-(2-Amino-l,2-diphenylethyl)-p- p-toluene sulfonamide ; and

b) treating the 3-((R) 1 -(hydroxyethyl)p phenyl ethyl(methyl)carbamate with amine in presence of methane sulphonylchloride to obtain (S)-3-(l- (dimethylamino)ethyl)phenylethyl(methyl) carbamate.

Or

a) reducing stereospecifically 3-acetylphenyl ethyl(methyl)carbamate to 3-((S) 1- (hydroxyethyl) phenyl ethyl(methyl)carbamate by reacting with compound selected from a group comprising complex of Phenyl boronic acid- Sodium borohydride - D(+) Tartaric acid and Ruthenium metal catalyst- prepared by reacting with Dichloro(p-cymene) ruthenium(II)dimer and ((iS,2S)-N-(p-Toluenesulfonyl)-l,2- diphenylethanediamine; and

b) treating the 3-((S) l-(hydroxyethyl)p phenyl ethyl(methyl)carbamate with dimethyl amine in presence of Phosphorous tribromide to obtain (S)-3-(l- (dimethylamino)ethyl)phenylethyl(methyl) carbamate.

In an embodiment of the present invention, the 3-((R) l-(hydroxyethyl)phenyl ethyl(methyl)carbamate is of chiral purity ranging from about 96% to about 98%.

In still another embodiment of the present invention, the 3-((S) l-(hydroxyethyl) phenyl ethyl(methyl)carbamate is of chiral purity ranging from about 95% to about 98%.

In yet another embodiment of the present invention, the (S)-3-(l-(dimethylamino)ethyl)phenyl ethyl (methyl) carbamate is of HPLC purity ranging from about 95% to about 99.5%.

The present invention is in relation to the preparation of (5)-3-(l-(dimethylamino)ethyl)phenyl ethyl (methyl)carbamate in two steps. The first step of the invention involves different embodiments to obtain (R) or (S) enantiomerically rich intermediate, 3 -(1 -hydroxy ethyl) phenyl ethyl(methyl)carbamate (Formula II) by reduction of 3-acetylphenyl ethyl(methyl)carbamate (I) and in the second step, conversion of said (R) or (S) isomer to the target (S) isomer in high yield and purity.

i?-isomer 5-isomer

(a) (b)

Formula II

The preparation of the (R) or (S) enantiomerically rich intermediate, 3 -(1 -hydroxy ethyl) phenyl ethyl(methyl)carbamate is carried out by reduction of 3-acetylphenyl ethyl(methyl)carbamate using a boronic acid complex obtained by reaction between phenyl boronic acid, sodium borohydride and L(+) Tartaric acid or D(+) Tartaric acid. While the complex involving L(+) Tartaric acid gave 3 -((R)-l -hydroxy ethyl) phenyl ethyl(methyl)carbamate ,the complex involving D(+) Tartaric acid gave 3 -((S)-l -hydroxy ethyl) phenyl ethyl(methyl)carbamate.

In another embodiment, chiral metal catalyst of Ruthenium is used for reduction to obtain the intermediate (II).

Specifically chiral catalyst obtained by Dichloro(p-cymene)ruthenium(II) dimer and (R,R)-N-(2- Amino-l,2-diphenylethyl)-p-toluenesulfonamide is used to derive 3 -((R)-l -hydroxy ethyl) phenyl ethyl(methyl)carbamate. While the (S) isomer of the 3 -(1 -hydroxy ethyl) phenyl ethyl(methyl)carbamate is obtained by the chiral metal catalyst of Dichloro(p- cymene)ruthenium(II) dimer and (lS,2S)-N-(p-Toluenesulfonyl)-l,2-diphenylethanediamine. In both the embodiments of reduction of 3-acetylphenyl ethyl(methyl)carbamate to the (R) or (S) isomer of 3-(l -hydroxy ethyl) phenyl ethyl(methyl)carbamate, the reaction proceeds with high yield of the specific isomer ranging from about 95% to about 98% and with high purity ranging from about 97.5% to about 99.5% as recorded by the HPLC. The 3-((R)l -hydroxy ethyl) phenyl ethyl(methyl)carbamate (II) is treated with dimethylamine in presence of methanesulphonylchloride to obtain (S)-3-(l-(dimethylamino)ethyl)phenyl ethyl (methyl)carbamate. In another embodiment, 3-((S)l-hydroxy ethyl) phenyl ethyl(methyl)carbamate (IIA) is treated with phosphorus tribromide in presence of dimethylamine to obtain the (S)-3-(l-(dimethylamino)ethyl)phenyl ethyl (methyl)carbamate. In both the embodiments the (R) or (S) isomer of 3 -(1 -hydroxy ethyl) phenyl ethyl(methyl)carbamate can be converted to specific (S)-3-(l-(dimethylamino)ethyl)phenyl ethyl (methyl)carbamate with an yield ranging from about 90% to about 96% purity being more than 99.5%.

The reactions proceed smoothly in solvents selected from a group comprising methylene dichloride, ethylene dichloride, methylisobutylketone, chloroform, and carbon tetrachloride. Scheme I provides the schematic diagrams of the preparation of the (S)-3-(l- (dimethylamino)ethyl)phenyl ethyl (methyl)carbamate in accordance with the above description. The invention is also in relation to the preparation of salts of (S)-3-(l-(dimethylamino)ethyl) phenyl ethyl (methyl)carbamate. Preferably Tartarate salt of the (S)-3-(l-(dimethylamino)ethyl) phenyl ethyl (methyl)carbamate by reacting with L(+) Tartaric acid.

(S)-3-(1 -(Dimethylamino)ethyl)phenyl ethyl(methyl)carbamateTartrate

3-acetylphenyl ethyl(methyl)carbamate

C _{1 2} H ₁₅ N0 ₃

Mol. Wt. : 221 .25

(I)

Chiral Reduction Chiral Reduction

(fl)-3-(1 -hydroxyethyl)phenyl

(S)-3-(1 -hydroxyethyl)phenyl

ethyl(methyl)carbamate ethyl(methyl)carbamate

C _{1 2} H ₁₇ N0 ₃ C _{1 2} H ₁₇ N0 ₃

Mol. Wt. : 223.27 Mol. Wt. : 223.27

(MA) (II)

(S)-3-(1 -(dimethylamino)ethyl)phenyl ethyl(methyl)carbamate

C-| 4H ₂₂ N ₂ 0 ₂

Mol. Wt. : 250.34

(HI) O OH

OH O

C _{1 8} H ₂₈ N ₂ Og

Mol. Wt. : 400.42

(S)-3-(1 -(dimethylamino)ethyl)phenyl ethyl(methyl)carbamateTartrate

(IV)

Scheme I Experimental:

The examples provided in this experimental section is only exemplary and does not limit the scope of the invention. A person skilled in the art may modify the conditions without deviating from the scope of the invention and all such deviations necessarily fall under the scope of the invention described herein.

A. Preparation of ( R)-3-(l-Hydroxyethyl)phenylethyl(methyl)carbamate (II)

Experiment 1

Phenyl boronic acid (13.6 gm 0.11 mol) and L+Tartaric acid (16.8 gm, 0.11 mol) is mixed in Acetonitrile 100 ml with presence of Calcium hydride( 9.4 gm 0.22 mol). This solution is refluxed for I hr.

Solution of I (20 gm 0.09 mol) in 100 ml Acetonitrile is added at 20-25. Sodium borohydride ( 4 gm 0.162 mol) is charged slowly and stirred at 20-25 °C for 8 hrs. After completion of reaction, Ice-water is charged 250 ml and extracted product in Methylene Dichloride 200 ml. The desired product R- isomer, 90% yield is isolated after distillation

Chiral HPLC: R isomer 97% S Isomer 3%, HPLC purity: 97.57%. (figures 1 and 2)

Experiment 2

Solution of I (30 gm 0.136 mol) and separately prepared catalyst charged {Catalyst Preparation; Dichloro(p-cymene)ruthenium(II) dimer 100 mg and (R,R)-N-(2- Amino- 1 ,2-diphenylethyl)-p- toluenesulfonamide 168 mg is mixed with DMF 5 ml and heated to 30 min.}. The reaction mass is heated to 70-75 °C slowly addition of Formic acid 75 ml (10% aqueous solution ) in 6-7 hrs. Water 200 ml charged at 25 °C after completion of reaction. Desired product II is isolated after distillation of Ethyl acetate with 95% yield . Chiral HPLC: R isomer 98% S Isomer 2% ; HPLC purity: 98.57% (figure 3 and 4).

B.Preparation of ( S)-3-(l-Hydroxyethyl)phenylethyl(methyl)carbamate ( (IIA)

Experiment 3

Solution of I (30 gm 0.136 mol) and separately prepared catalyst charged {Catalyst Preparation; Dichloro(p-cymene)ruthenium(II) dimer 90 mg and (lS,2S)-N-(p-Toluenesulfonyl)-l,2- diphenylethanediaminel60 mg is mixed with DMF 2 ml and heated for 40 min.} . The reaction mass is heated to 70-75 °C slowly with addition of Formic acid 65 ml (10% aqueous solution ) in 6-7 hrs. Water 200 ml charged at 25 °C after completion of reaction. Desired product II is isolated after distillation of Ethyl acetate got 3-((S)-lHydroxyethyl) phenyl ethyl(methyl)carbamate 97% yield.

Chiral HPLC: R isomer 4.33% S Isomer 95.6% , HPLC purity: 99.52% (Figures 5 and 6) Experiment 4

Phenyl boronic acid (13.6 gm 0.11 mol) and D-Tartaric acid (16.8 gm, 0.11 mol) is mixed in Acetonitrile 100 ml with presence of Calcium hydride( 9.4 gm 0.22 mol). This solution is refluxed for 1 hr. Solution of I (20 gm 0.09 mol) in 100 ml Acetonitrile is added at 20-25. Sodium borohydride ( 4 gm 0.162 mol) is charged slowly and stirred at 20-25 °C for 8 hrs. After completion of reaction, Ice-water is charged 250 ml and extracted product in Methylene Dichloride 210 ml. The desired product (III) 91% yield is isolated after distillation.

Chiral HPLC: R isomer 2.5% S Isomer 97%: HPLC purity: 98.17% (Figures 7 and 8).

C. (S)-3-(l-(dimethylamino)ethyl)phenylethyl(methyl)carbamate (Formula A)

Experiment :5

Solution of II( Obtained from expt no 1 or 2) (10 gm 0.44 mol) in Methylene Dichloride 100 ml and Triethyl amine (12.5 gm 0.277 mol) is chilled to 0-5° C. Methane sulphonylchloride (6 gm 0.52 mol) added and stirred for 3 hrs. Dimethyl amine solution 50 ml (40%) is charged and stirred for 8 hrs. Organic layer is acidified and extracted with Ethyl acetate 100 ml in basic ph. After evaporation solvent desired product isolated 72% yield.

Chiral HPLC: R isomer 4.33% S Isomer 95.6% HPLC purity: 99.52% (figures 9 and 10) Experiment :6

Solution of compound IIA from ( 5 gm 0.022 mol) in Methylene Dichloride 25 ml chilled to 0-5 °C. To this solution, Phosphorous tribromide (3.5 gm 0.012 mol) added and stirred for 2 hrs. Organic layer is distilled after water wash sodium carbonate solution. To residue ( 5 gm) added Methylene Dichloride ( 50 ml) and Dimethyamine 40% solution (50 ml) at 0-5°C. The reaction mass stirred for 8 hrs.

Organic layer is extracted in Ethyl acetate at alkaline medium. After evaporation of solvent (III) obtained 95% yield.

Chiral HPLC: R isomer 10% S Isomer 90% HPLC purity: 95.52% (figures 11 and 12)

D. (S)-3-(l-(dimethylamino)ethyl)phenylethyl(methyl)carbamate Hydrogen Tartrate (IV) Experiment 7

L+Tartaric acid ( 4 gm 0.026 mol) in Acetone 60 ml is refluxed for 30 min. Solution of III (6.6 gm 0.026 mol) in Acetone 60 ml is added to above solution. The mass is stirred for 2 hrs and filtered at 0-5°C. The wet cake is refluxed in Acetone 40 ml. Final product is isolated after cooling to 0-5°C followed by acetone wash. Obtained yield 75%.

Chiral HPLC: R isomer 0.21% S Isomer 99.8% HPLC purity: 99.92% (figures 13 and 14) Experiment 8

L+Tartaric acid ( 8gm 0.052 mol) in Methanol 20 ml and Solution of III (13.5 gm 0.061 mol) in Ethyl acetate 60 ml is added to above solution at 50-60°C. The mass is stirred for 2 hrs at 20- 25 C and filtered at 0-5 C. The wet cake is refluxed in Acetone 100 ml. Final product is isolated after cooling to 0-5°C followed by acetone wash. Obtained yield 76%.

Chiral HPLC: R isomer 0.19% S Isomer 99.8% HPLC purity: 99.98% (figures 15 and 16). The invention is very cost effective due to near complete conversion of the commercially available starting reagent, 3 -acetyl phenyl ethyl(methyl)carbamate, with minimum wastage and avoidance of any further resolution of racemic mixtures. The cost effective, environmentally tolerable reagents and process renders the invention to be industrially scalable disseminating new hope on the reduction in the cost of Rivastigmine drug.